Friday, March 24, 2023

Lupine Publishers| Semaglutide versus liraglutide for treatment of obesity

 Lupine Publishers| Journal of Diabetes and Obesity


Abstract

Background: Once weekly (OW) semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) currently under evaluation for treatment of obesity at a dose of 2.4 mg OW.

Objective: To compare weight-loss efficacy and safety of once daily (OD) liraglutide 3.0 mg versus OW semaglutide 2.4 mg. Methods: Pubmed research up to March 31, 2021. Randomized trials, pertinent animal studies, and reviews are included. Search terms were glucagon-like peptide-1 receptor agonists, weight loss, obesity, liraglutide, semaglutide, efficacy, safety.

Results: No head to head trials are available to provide direct comparison of efficacy of OD liraglutide 3.0 mg versus OW semaglutide 2.4 mg. However, marked resemblance between trials in terms of study protocols and subjects’ characteristics may allow indirect comparison. In clinical trials of OW semaglutide, this drug was consistently associated with greater weight loss than in trials of OD liraglutide. Thus, placebo-corrected percentage weight reduction was -10.3 to -12.4% and -5.4% with OW semaglutide and OD liraglutide, respectively. In patients with type 2 diabetes, corresponding weight reduction was less pronounced with both drugs being -6.2% and -4.3% with OW semaglutide and OD liraglutide, respectively. In addition, head to head trials comparing liraglutide and semaglutide used in different doses and formulations consistently showed more weight loss in favor of semaglutide. In general, the anti-hyperglycemic efficacy and safety profile are similar in both drugs.

Conclusions: Available indirect evidence suggests that OW semaglutide 2.4 mg may be superior to OD liraglutide 3.0 mg for weight loss. Head-to-head comparison between these 2 agents is essential to confirm this conclusion.

Keywords: Obesity; Liraglutide; Semaglutide; Glucagon-like Peptide-1; Efficacy; Safety; Weight Loss; Type 2 Diabetes; Hemoglobin A1c

Introduction

GLP-1 RAs are approved for treatment of type 2 diabetes. The drug profile of these drugs is characterized by mild dose-related weight loss of approximately 2-6 kg [1]. Currently, liraglutide is the only GLP-1 RA approved for treatment of obesity in a dose higher than that approved for type 2 diabetes (3.0 mg daily for treatment of obesity as opposed to a maximum dose of 1.8 mg/d in type 2 diabetes) [2]. Semaglutide is another GLP-1 RA approved for treatment of type 2 diabetes in a dose of 0.5-1.0 mg given subcutaneously OW and as an oral formulation in a dose up to 14 mg once daily [3,4]. Currently, semaglutide is under evaluation for future approval for treatment of obesity. The Semaglutide Treatment Effect in People with obesity (STEP) development program including 5 phase 3 clinical trials (STEP 1 to 5) was launched to evaluate efficacy and safety of OW semaglutide at this high dose of 2.4 mg for treatment of obesity in patients with and without diabetes [5].

Mechanisms of Weight Loss by Liraglutide and Semaglutide

In general, the mechanisms of weight loss by liraglutide and semaglutide are similar. Both agents were shown to reduce appetite and hunger while increasing sense of fullness and satiety [6,7]. In addition, OW semaglutide 2.4 mg, but not liraglutide, may decrease food craving [7]. Animal studies have shown that the anorexigenic effect of semaglutide is mediated by GLP-1 receptors in the hypothalamus and hind brain [8,9]. Delay in gastric emptying, a class effect of all GLP-1 RAs, may contribute to the sensation of early fullness [10]. Meanwhile, one study with relatively longfollow- up (52 weeks) has shown that improvements in hunger and fullness with OD liraglutide 3.0 mg peak after 4 weeks, then decline gradually and return to baseline after 40 weeks [6]. Similar followup studies are not available for semaglutide.

STEP Program of Semaglutide

STEP 1 to 4 trials are well-designed studies comparing OW 2.4 mg semaglutide with placebo in obese individuals (defined as BMI of ≥ 30 kg/m2, over ≥ 27 kg/m2 with ≥ 1 weight-related coexisting condition e.g. hypertension, dyslipidemia, cardiovascular disease, or obstructive sleep apnea) for 68 week-duration [11-14]. STEP 1, 3 and 4 excluded patients with diabetes, whereas STEP 2 included exclusively patients with type 2 diabetes [11,13-14]. In addition, STEP 2 included a third group of individuals randomized to the smaller anti-diabetic dose of OW semaglutide 1.0 mg [12]. In STEP 1, 2 and 4, all participants receive lifestyle intervention defined as a 500 kcal deficit relative to the estimated energy expenditure plus encouragement of increase physical activity, such as walking 150 minutes per week. In STEP 3 trial, all subjects received a low-calorie diet (1000-1200 kcal/d) provided as meal replacement for the first 8 weeks. Subsequently, they were transitioned to a low-calorie diet (1200-1800 kcal/d) of conventional food. Moreover, they were prescribed 200 min of physical activity/week [13]. The coprimary endpoints of STEP 1 to 3 trials were the percentage change in body weight and weight reduction of at least 5% at week 68 compared with placebo [11-13]. STEP 4 trial was a withdrawal trial that includes an initial run-in period of 20 week during which all subjects received OW semaglutide 2.4 mg followed by randomization to a group that continued the drug and another group that switched to placebo for further 48 weeks [14]. Overview of STEP 1 to 4 trials are summarized in (Tables 1 and 2).

Table 1: Weight-loss efficacy of liraglutide and semaglutide in patients without diabetes.

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Abbreviations: W: Women; BMI: Body Mass Index; L: Liraglutide; S: Semaglutide; OW: Once Weekly; PL: Placebo; HbA1c: Hemoglobin A1c; CI: Confidence Intervals

Table 2: Weight-loss efficacy of liraglutide and semaglutide in patients with type 2 diabetes

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Abbreviations: PL: Placebo; W: Women; HbA1c: Hemoglobin A1c; L : Liraglutide; OWS: Once-Weekly Semaglutide

Weight loss in Semaglutide and Liraglutide Trials

While no head to head trials are available to compare weight loss efficacy of OW semaglutide 2.4 mg with OD liraglutide 3.0 mg, indirect comparison may be inferred from results of their respective trials. In fact, as shown in tables 1 and 2, subjects’ characteristics at baseline in these trials were similar to a great extent (Table 1). In addition, the study protocols and designs have several common features (e.g. similar primary end point). In STEP trials 1, 3 and 4 that excluded patients with diabetes, the difference in weight loss between OW semaglutide and placebo ranged between -10.3% and -12.4% at 68 weeks (Table 1). Meanwhile, in the SCALE Obesity and prediabetes trial of OD liraglutide 3.0 mg, the corresponding difference was -5.4% (95% CI, -5.8 to -5.0%) at 56 weeks (Table 1) [15]. In trials that exclusively recruited patients with type 2 diabetes, the weight loss efficacy of both drugs was diminished, but was still relatively greater in OW semaglutide 2.4 mg than with OD liraglutide 3.0 mg. Thus, in 2 liraglutide diabetes trials, the mean difference in weight loss between the drug and placebo was -4.0 and -4.3%, whereas the corresponding difference was -6.2% with OW semaglutide 2.4 mg (Table 2) [12,16-17]. The explanation of this finding is unclear but might be related to the coexistence of type 2 diabetes, relatively older patient population (mean age approximately 55 year-old in diabetes trials versus 45 year-old in trials excluding diabetes), or the lower baseline body weight (approximately 99.8 kg in diabetes trials versus approximately 105.5 kg in non-diabetes trials) (Tables 1-2) [12,16-17]. Other parameters that suggest superiority of OW semaglutide 2.4 mg over OD liraglutide 3.0 mg are the proportions of individuals losing ≥ 5% and > 10% of body weight. These proportions were always higher in trials of semaglutide than in those of liraglutide (Tables 1 and 2).

Head to Head Trials of Semaglutide Versus Liraglutide

Another indirect line of evidence suggesting greater efficacy of semaglutide compared to liraglutide may be derived from 3 randomized head to head trials comparing the 2 agents in different doses and formulations. A randomized, placebo-controlled, doubleblind trial [18] compared semaglutide in 5 daily subcutaneous doses (0.05, 0.1, 0.2, 0.3, and 0.4 mg) versus liraglutide 3.0 mg once daily on top of lifestyle changes in obese subjects without diabetes. After 52 weeks, mean weight reduction from baseline was significantly greater in patients randomized to semaglutide doses ≥ 0.2 mg daily being - 11.2 to -13.8% versus -7.8% in subjects randomized to liraglutide 3.0 mg daily [18]. The second trial including patients with type 2 diabetes [19] compared oral semaglutide (14 mg qday) with OD liraglutide 1.8 mg in doubleblind double-dummy fashion. After 26 weeks, oral semaglutide resulted in superior weight loss (-4.4 kg) compared with liraglutide (-3.1 kg), estimated difference -1.2 kg (95% CI, -1.9 to -0.6, P= 0.001) [19]. The third trial [20] compared OW semaglutide 1.0 mg with liraglutide 1.2 mg in patients with type 2 diabetes in an open-label design. After 30 weeks, mean weight loss was -5.8 kg and -1.9 kg, in the semaglutide and liraglutide groups, respectively; estimated treatment difference -3.8 kg (95% CI, -4.47 to -3.09, P<0.0001) [20]. Taken together, the results of the preceding 3 trials suggest higher efficacy of semaglutide than liraglutide irrespective of doses or drug formulation (i.e. subcutaneous or oral semaglutide).

Anti-Hyperglycemic Efficacy of Liraglutide Versus Semaglutide

The difference between semaglutide and liraglutide with respect to their anti-hyperglycemic efficacy is not as consistent as in their weight-loss effects. Thus, in the studies conducted by O’Neil et al, [18] and Pratley et al [19], semaglutide was similar to liraglutide in HbA1c reduction. Meanwhile, in the trial conducted by Capehorn et al, [20], OW semaglutide 1.0 mg was superior to liraglutide 1.2 mg qday; estimated treatment difference in HbA1c reduction was - 0.69% in favor of semaglutide. However, the latter trial is limited by its open-label design and using liraglutide in submaximal antidiabetic dose (1.2 mg instead of 1.8 mg) [20]. Therefore, while semaglutide may be more effective than liraglutide in causing weight loss, both GLP-1 RAs may be equally effective in terms of glycemic control.

Effects of Semaglutide and Liraglutide on Cardiovascular Variables

Significant reduction in systolic blood pressure (SBP) was recorded in subjects randomized to semaglutide in STEP 1-3 trials, approximately 4-5 mmHg lower than in individuals randomized to placebo [11-13]. Likewise, a significant reduction in DBP of approximately 2 mmHg was observed in STEP 1 and 3 trials [11,13]. Changes in lipid panel were generally mild. Thus, reduction in plasma triglycerides of 14-17% compared to placebo was the most consistent change in lipid panel. Minor reductions in concentrations of low-density lipoprotein-cholesterol (LDL-C) (by ≤7% vs placebo) and increase in high-density lipoprotein-cholesterol (HDL-C) levels (by <5% vs placebo) were also observed. In addition, there was significant reduction in the inflammatory marker C-reactive protein (CRP) levels in semaglutide-treated subjects vs placebo [11-13]. Similar beneficial changes in the above cardiovascular (CV) markers were described in liraglutide trials albeit they were lesser in magnitude [15,21]. The above favorable changes in blood pressure, lipids and CRP are likely attributed to weight loss per se and are unlikely to be direct effects of semaglutide or liraglutide.

Safety of Liraglutide and Semaglutide as Anti-Obesity Agents

Gastrointestinal Adverse Effects

Gastrointestinal (GI) adverse effects represent the most common adverse events that characterize all GLP-1 RAs. In liraglutide obesity trials, GI adverse events occurred in 65% and 39% of subjects randomized to OD liraglutide 3.0 mg and placebo, respectively [16]. In STEP 1-3 trials of semaglutide, GI adverse effects were reported by approximately 63-83% and 34-63% in subjects randomized to OW semaglutide and placebo, respectively [11-13]. Among the GI adverse effects, nausea was the most common, followed by diarrhea, vomiting and constipation [11-13,16]. The frequency of GI symptoms increased early in the first few weeks during drug titration. They were generally described as mild to moderate and transient. However, in a minority of patients, they can be severe. In fact, GI adverse effects were the most frequent cause of premature drug withdrawal. Thus, in the largest obesity trial of liraglutide, drug discontinuation due to GI adverse effects occurred in 6.4% and 0.7% in the liraglutide and placebo group, respectively [15]. In STEP trials, withdrawal due GI adverse events occurred in 3.4-4.5% and 0-1.0% in patients randomized to OW semaglutide and placebo, respectively [11-13]. Previous trials including patients with type 2 diabetes using OW 1.0 mg semaglutide have shown that GI adverse effects tend to be more common with semaglutide compared with other GLP-1 RAs [1]. Meanwhile, post-hoc analysis by Lingway et al [1] suggest that GI adverse effects contribute minimally (less than 0.1 kg) to the superior weight loss effects of semaglutide vs other GLP-1RAs. Incidence of cholelithiasis and cholecystitis was slightly higher with liraglutide than placebo, 1.5% and 0.4%, respectively [15] as well as with semaglutide than with placebo, 2.5-2.6% versus 0-1.2% [11-13]. These events may be attributed in part to weight loss, but other mechanisms could be involved such as inhibition of gallbladder contraction and biliary motility [22]. Frequency of acute pancreatitis is marginally elevated with OD liraglutide 3.0 mg (1.3% vs 1.0 in placebo) [21], and similar to placebo in trials of OW semaglutide 2,4 mg in STEP 1 to 4 trials [11-14].

Hypoglycemia

Consistent with the glucose-dependent action of GLP-1 RAs, frequency of hypoglycemia was similar to placebo in patients without diabetes. However, in obesity trials including patients with type 2 diabetes, frequency and severity of hypoglycemia were increased with use of OD liraglutide 3.0 mg (87 versus 31 events per patients-year with placebo) [16]. These hypoglycemia events occurred mainly in patients using sulfonylureas [16]. In STEP 2 trial, severe or blood-glucose confirmed symptomatic hypoglycemia occurred in 5.7% and 3.0% of patients receiving OW semaglutide 2.4 mg and placebo, respectively [12].

Safety Concerns about Liraglutide and Semaglutide

There was numerical increase in breast neoplasms in association with OD liraglutide 3.0 mg. Thus, 10 premalignant and malignant neoplasms were reported in 9 women in the liraglutide arm versus none in the placebo arm [21]. In STEP 4 trial of OW semaglutide 2.4 mg, 3 breast cancers were diagnosed in women randomized to semaglutide versus none in the placebo group [13]. Worsening diabetic retinopathy seems to be an adverse effect specific to semaglutide which was initially observed in association with use of OW semaglutide 0.5-1.0 mg [23]. In STEP 2, there was a trend towards increase in incidence of retinal disorder events in the 2 semaglutide arms compared with the placebo arm [12]. Thus, these events occurred in 6.9%, 6.2%, and 4.2% in patients randomized to OW semaglutide 2.4 mg, OW semaglutiude 1.0 mg, and placebo, respectively [12].

Appraisal of Liraglutide and Semaglutide

Although available data suggest that OW semaglutide 2.4 mg may be more effective than daily liraglutide 1.8 mg in weight reduction, both drugs offer several advantages for management of obesity. First, their short-term efficacy and safety are supported by well-designed randomized trials [11-15]. Second, being also wellstudied as anti-diabetic drugs, they may be particularly useful in obesity-related type 2 diabetes by causing reduction of both body weight and hyperglycemia [12]. Furthermore, in individuals with pre-diabetes, they delay the onset of type 2 diabetes and increase reversion to normoglycemia [15,21]. The OW administration of semaglutide might virtually enhance compliance with prolonged use. However, both agents have several limitations. First, the common occurrence of GI adverse effects which not uncommonly lead to drug discontinuation. Second, safety beyond 58 weeks is not available for OW semaglutide 2.4 mg [11-14]. The ongoing STEP 5 may in part clarify this problem as it extends over a 2-year period [5]. In case of OD liraglutide 3.0 mg, safety data from placebocontrolled trials are overall reassuring and extend up to 172 weeks [21]. Third, the durability of the weight loss effect is still unclear. In fact, maximum weight loss with use of either drug was achieved after approximately 52 weeks followed by a gradual rebound [11- 15, 21]. Moreover, after drug cessation, weight regain takes place at a more rapid pace along with rise of systolic blood pressure and glycemic parameters to their baselines [14,16]. Hence, these drugs will be taken for years, or even decades as long as weight loss is desired. It is crucial therefore to establish their long-term safety. Fourth, drug cost is another limitation. Advantages and limitations of both agents are summarized in Table 3.

Table 3: Advantages and limitations of liraglutide and semaglutide for treatment of obesity.

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Conclusions and Current Directions

Available clinical trials suggest that OW semaglutide 2.4 mg as an adjunct to healthy life-style changes may be more effective than OD liraglutide 3.0 mg in terms of weight reduction, but not glycemic control. While no head to head comparison is available yet, data derived from respective trials of liraglutide and semaglutide showed superior weight loss with use of OW semaglutide 2.4 mg. Furthermore, head to head comparison of the 2 drugs used in different doses or formulations, consistently showed greater weight loss associated with the use of semaglutide than with liraglutide. However, the superiority of OW semaglutide 2.4 mg will only be confirmed by direct head to head comparison with OD liraglutide 3.0 mg in the setting of randomized, double-blind and double-dummy trials. The possible increase in incidence of breast cancer in association with these 2 agents must be clarified in long-term studies and post-marketing investigations. Similarly, risk of worsening of diabetic retinopathy in relation to the use of semaglutide should be carefully examined. Whereas both drugs in their anti-diabetic doses may reduce CV events in patients with type 2 diabetes, it is equally important to assess their impact on CV outcomes when used in their higher doses for treatment of obesity. In this regard, the SELECT study is an ongoing, double-blind placebo-controlled trial specifically designed to examine the effect of OW semaglutide 2.4 mg on CV outcomes in overweight and obese persons with established CV disease who do not have diabetes [17]. SELECT study started in November 2018 and is expected to recruit 17,500 participants, and last for approximately a total of 59 months.

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Thursday, November 24, 2022

Happy Thanksgiving!!

 Greetings from Archives of Diabetes and Obesity (ADO)


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Monday, July 18, 2022

Effectiveness, Safety and Therapeutic Adherence of Weekly Subcutaneous Semaglutide for Weight Management in Real Practice: An Observational Study

 

Abstract

Aims: To evaluate in a real practice setting effectiveness, safety and adherence to weekly subcutaneous semaglutide for weight reduction, along with diet and lifestyle modifications in obese/overweighted patients attending an Obesity Unit.
Materials and Methods: In a retrospective study, 367 patients (mean age 50.25 years, 78.36% female, mean baseline body mass index 32.39 kg/m2) were followed for 10.7 months (median) after initiation of semaglutide. Up to 24.25% of patients were previously on GLP-1 analogue therapy (mostly liraglutide) and 36.26% used background oral medication for weight loss.
Results: At final office visit patients averaged a weight loss of 7.97±3.42 kg (9.13±3.86% baseline body weight) and 88.07% and 30.27% of patients had achieved a≥5% and ≥10% weight loss, respectively, as compared to baseline body weight. Up to 61.19% and 33.46% of patients maintained 0.5 and 1.0 mg dose, respectively and 86.18% of patients persisted on sc semaglutide by last office visit. Nausea and abdominal pain were reported by 12.53% of patients with no severe adverse events. Background antiobesity medication did not affect weight loss and patients on previous GLP-1 analogue therapy lost 1.43 kg less than naïve patients (p<0.001).
Conclusions: Out-of-label weekly administration of sc semaglutide 0.5 to 1.0 mg resulted in a significant, safe and affordable weight loss in a pragmatic setting without reimbursement of treatment cost. Magnitude of weight loss and safety profile was in line with preliminary data from a phase 2 trial, although this will need to be confirmed by an ongoing phase 3 development programme.

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Friday, March 25, 2022

Lupine Publishers| The Effect of Glibenclamide Administration on Gastrin Release in Diabetic Patients

 Lupine Publishers| Journal of Diabetes and Obesity


Abstract

The effects of sulfonylureas on gastrointestinal function in man is not yet quite clear. The aim of this study was to investigate the effect of oral administration of glibenclamide on gastrin release in patients with non-insulin dependent diabetes mellitus. Twelve non-insulin dependent diabetic patients (six men, six women, median age 57 years, range 46-63 years) were studied. Glibenclamide or placebo were given on different days and in a random order 10 minutes before a standard meal (73.6 g corned beef + 5ml olive oil + 60g bread). Blood samples for the determination of gastrin, glucose and C-peptide in serum, before (-15 and 0 minutes) and 30, 60 , 90 , 120 and 180 minutes after the standard meal, were obtained. Initial mean values of gastrin in serum did not differ significantly between the two meals. As expected gastrin levels increased significantly after taking the meals. However, no significant differences concerning mean gastrin concentrations between the two meals were noted at all time intervals studied, although there was a trend for the glibenclamide-preceded meal to exert lower gastrin values, especially at 60 minutes (p: 0,06). Mean serum glucose levels were, as anticipated, significantly lower after the glibenclamide-meal. Similarly, serum C-peptide concentrations were higher after this meal. It is concluded that acute glibenclamide oral administration does not influence post-stimulatory 3 gastrin levels in non-insulin dependent diabetic patients. Thus, in the clinical situation, sulfonylurea administration does not seem to interfere with gastrin release.

Introduction

The effect of PPIs (Proton Pump Inhibitors) on serum gastrin levels has been well known since the early years of patient treatment with omeprazole [1]. On the contrary, the effects of sulfonylureas on gastrointestinal function in man is not yet quite clear. Sulfonylureas are known to have various extrapancreatic actions [2]. In addition to their stimulatory effect on insulin release from pancreatic islets. However, the effects of sulfonylureas on gastrointestinal function and gut hormones release remain unclear. More specifically, as it regards gastrin, there are only a few studies in which the effect of sulfonylureas is investigated [3,4]. furthermore, these studies show a discrepancy between results obtained in man and animal models [5,6] and, in addition they describe only the effect of sulfonylureas on fasting and not the postprandial serum gastrin concentrations [3,4]. The present study was undertaken, therefore, to investigate the effect of glibenclamide oral administration in patients with Non-Insulin Dependent Diabetes Mellitus (NIDDM) in combination with a test meal.

Results

Initial mean values of gastrin in serum did not differ significantly between the two meals and were within the normal range (<90 pmol.1). As expected, gastrin levels increased significantly after taking the meals (Table 1). However, no significant gastrin concentrations between the two meals (meal + glibenclamide and meal + placebo) at all intervals studied, although there was a trend for the glibenclamide-preceed meal to exert lower gastrin values, especially at 60 minutes (p:0.063) (Table 1). Blood glucose variations are summarized in (Table 2). Mean serum glucose levels were, as anticipated significantly lower after the glibenclamide-meal as compared to those after placebo-meal. Similarly, postprandial C-peptide concentrations in serum were significantly higher after the glibenclamide-meal comparing to the placebo-meal (Table 3).

Table 1: Mean serum gastrin values ±SD (pmol/l).

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Table 2: Mean serum glucose levels ± SD (mg/dl).

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Table 3: Mean serum C-peptide concentrations ± SD (ng/dl).

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Discussion

In this study, gastrin concentrations in serum were found not to be altered significantly in NIDD patients after oral administration of glibenclamide, in combination with a meal, as compared to those who received the same meal with placebo. Although there was a trend for patients taking glibenclamide to present lower postprandial serum gastrin levels, this difference was not statistically significant. These findings are in agreement with the results of a previous study in which injectable solution of glibenclamide was administered intravenously or per os to healthy volunteers [3]. In the above study, gastrin levels were estimated in periphal and portal blood and were found to be essentially unchanged, under all conditions studies [3]. In another study, tolbutamide was reported to inhibit gastrin release in man [4]. In that case the drug was administrated intravenously or per so to normal subjects as well as in patients with atrophic gastritis, duodenal ulcer and IDDM [4].

Our study Differs from the previous reports:

a) Because it concerned exclusively patients with NIDDM, who are mainly treated with glibenclamide and

b) In the parallel administration of a test meal.

Therefore, it is obvious that the present study was planned accordingly to simulate the everyday conditions in diabetic patients taking a meal in combination with glibenclamide. These results, as well as the above-mentioned study [4], suggest a possible inhibition of gastrin release by Sulfonylureas in man. However, in animal models, gastrin release has been reported to be stimulated by sulfonylureas [5,6]. Indeed tolbutamide was found to stimulate both somatostatin and gastrin secretion from the isolated perfused rat stomach [5]. Also, glibenclamide was reported to stimulate gastrin release from the antral mucosa of cats [6]. It is possible that differences in animal species, as well as in the experimental design and drug dosage may account for this discrepancy. Basal gastrin values of diabetic patients in the present study were in normal range. Hupergastrinaemia has not been reported previously in diabetic humas, except in the diabetic pesuedo-Zolinger-Ellison syndrome [7] and a number of patients with clinical manifestations of autonomic neuropathy [8-10]. It has been further suggested that increased serum gastrin leels in those NIDD patients are not related to hypochlorhydria but, instead, are resulting from the autonomic dysfunction [8,9]. In the present study, patients did not show clinical manifestations of autonomic neuropathy. This, as well as the fact that they did not have impaired renal function, might well explain the normal initial mean gastrin values. Finally, it is noted that the present experiments deal with acute glibenclamide administration. Also, it would be interesting to investigate further the possible effect of sulfonylureas on gastrin levels in diabetic patients presenting hypergastrinaemia.

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Friday, February 25, 2022

Lupine Publishers| An Evidence-Based Herbal Supplement for The Control of Metabolic Syndrome

 Lupine Publishers| Journal of Diabetes and Obesity


Abstract

Background: Metabolic Syndrome (MS): Overweight, Obesity, Hypertension, Hyperglycemia and Hypercholesterolemia, are generally accepted today as clinical signals leading to cardiovascular diseases. Control of MS is therefore of a common health concern. While drug treatment is yet not available or may not be creditable, developing an effective health supplement against MS is highly justified.

Methods: A herbal formula composed of four herbs known to have anti MS pathological effects was used for in vivo and in vitro biological researches to verify its pharmacological effect, and subsequent pilot clinical trial.

Results: In vitro study: Adipocyte viability and cholesterol uptake, liver cell viability and anti-glycaemia effects, all gave positive results of good control. In vivo study testing herbal formula’s effects on obese mice also showed very promising results. In clinical trial, measurements of body weight, body circumferences, BMI, as well as liver fibrosis, all showed good responses after the herbal formula consumption.

Conclusion: Our efforts on the creation of an Evidence-Based Specific Supplement for the control of Metabolic Syndrome have harvested highly positive data in the laboratory. The subsequent 3 months’ pilot clinical trial showed positive data on the control of blood lipids, general body measurements and liver steatosis.

Keywords: Gene Expression; Lipid Droplets; Mitochondria; RNA Sequencing; Type 2 Diabetes Mellitus

Introduction

As cardiovascular diseases have become dominant causes of mortality, other related pathological presentations are gaining public attention [1,2]. Obesity is the commonest observable indicative of “unhealthiness”, leading to cardiovascular problems. Thus, simple objective measurements of obesity like Body Mass Index (BMI), blood lipids and cholesterols are also gaining much public concern [3]. Blood pressure and blood sugar levels naturally fall into the same checklist of safety requirements which are mainly affecting cardiovascular health [4].
As time goes on, the five major influences on cardiovascular health have thus been put together as the “Metabolic Syndrome” (MS): overweight, obesity, hypertension, hyperglycemia and hypercholesterolemia [5]. Another associated pathology, viz. fatty liver, turns up, as many sufferers of MS are found to have different degrees of liver dysfunction and fat deposits gradually leading the way to liver fibrosis [6].
For decades, varieties of interventions are available for the control of the different aspects of MS, particularly in areas that require specific effective control like hypertension and hyperglycemia. It is realized now that a better way to deal with the problem is to broaden the area of concern so that MS can be taken together in a multi-facetted preventive endeavor. Although specific single target pharmaceuticals are available for solitary treatment, a more ideal alternative could be some extra-pharmaceutical multiple target, harmonizing supplement to take care of all components of the MS [7,8].

Medicinal Herbs

A number of Medicinal herbs have been traditionally used as supplement for patients with diabetes mellitus and obesity. They are chosen for our study on metabolic syndrome. Platform studies would include bioactivities related to cardiovascular problems [9,10].
We selected four edible herbals items for the Chinese pharmacopeia to be tested. They are: (Table 1).

Table 1: Four edible herbals items for the Chinese pharmacopeia to be tested.

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The combined formula (2MSC) would be tested for the control of body fat and sugar metabolism, while its effects on blood pressure, blood lipids and liver function would carefully be studied [17]. The design of this study on MS has chosen an emphasis on the effects on fatty liver [18].

Methods

Preclinical Studies

In vitro experiments included the following:

To investigate specific bioactivities of individual herbs and the combined formula

I.Testing the effects of Crataegus Fructus and the formula on the adipocyte viability and cholesterol uptake using adipocyte and cacocell cultures [19].

II.Testing the effects of Schisandra Fructus and Silymarim Marianum separately and the combined formula on liver cell viability using HepG2 cells [20].

III.Testing the antiglycemic effects of Momordica and the combined formula using Brush Border Membrance Vesicle model via its glucose uptake obstruction [21-23].

In vivo Experiments

Male C578 1/6 mice were use. Obesity induction was achieved using forced high-fat feeding for 8 weeks. The obese mice were treated with normal diet and continual high fat diet with 2% and 4% combined herbal formula [18]. At the end of 8 weeks for the low dose and 12 weeks for the high dose, the animals were sacrificed to have comprehensive checks on Body Weight, Blood examinations for lipid assessments and liver examinations.

Results of Laboratory Studies

In Vitro Studies

3T3-L1 preadipocytes differentiation cell assay showed the effects of the different concentrations of 125 μg/ml, it was a dose that induced significant toxicity to cells, and there was no dose– response effect observed [19].
Fluorescent tagged cholesterol-treated Caco-2 cell assay

The effect of the different concentrations of Crataegus Fructus aqueous extract and the herbal formula extract on cholesterol uptake in Caco-2 cells. Crataegus Fructus aqueous extract significantly prevented the cholesterol uptake in Caco-2 cells in a dose dependent manner. Herbal formula extract on the other hand had no significant effect on the cholesterol uptake in Caco-2 cells [19].

Animal Studies

The body weight, adipose tissues weight and liver weight were measured. In the 8-week treatment study, the High-fat diet (HF-fed) animals significantly gained more weight than chow-fed animals. Among all HF-fed animals, there was a trend for a reduction in body weight of 4% among herbal formula fed animals, starting from week 9 onwards. Three types of adipose tissues (epididymal fat, peri-renal fat, and inguinal subcutaneous fat) were isolated and weighed. High-fat diet induced obesity in mice compared to normal chow-fed mice after 16 weeks and 20 weeks, as evidenced by the significant increase in all three types of fat pad mass to body weight ratio: epididymal fat pad (p < 0.01 for both 8-week and 12-week treatment studies), inguinal fat pad (p < 0.01 for both 8-week and 12-week treatment studies), and perirenal fat pad (p < 0.001 for both 8-week and 12-week treatment studies).
Livers were isolated, weighed and presented as liver to body weight ratio. High-fat diet induced an increase in liver to body weight ratio in both 8-week and 12-week treatment studies [19]. 2% and 4% herbal extracts dose-dependently reduced the liver to body weight ratio in both treatment periods.

Liver histopathology and inflammation assessment

Livers from mice fed on different diets were analyzed histologically. Normal-chow-fed animals demonstrated the histological sections of normal livers. In contrast, H&E sections from HF animals revealed the presence of a large number of circular lipid droplets within the hepatocytes. These lipid inclusions were clearly reduced in size as well as number in the livers of all herbal formula treated animals.

A Pilot Clinical Trial

Title: Pilot Clinical Study to evaluate the effects of the innovative herbal formula 2MSC in subjects with Metabolic Syndrome.

Hypothesis: 2 MSC is effective for the Management of MS, with particular emphasis on liver fibrosis (Fatty liver).

Study Design

An open label pilot study conducted with 30 overweight adult men and women were assigned to take 2 MSC daily for 3 months.

Study Population

Subjects recruited were 40-66 years of age, with BMI between ≥25kg/m2 and ≤37.7kg/m2. They agreed to attend all study visits and to keep their normal dietary habits and usual physical activities. Subjects were excluded if they were diabetic (on diabetic medication for more than four weeks); on cardiac and statin related drugs; on immune-suppressive drugs. Cigarette smokers, pregnant or lactating women were excluded. A total of 30 volunteers with no past history of allergy to herbal medicine were recruited.

Study Procedures

The study started after signing the proper consent. Duration of treatment lasted 12 weeks. Monthly phone calls were conducted to monitor the progress, compliance and adverse effects. Volunteers were reminded to keep their usual dietary habits and physical activities.

Data Collections

Demographic and basic measurements related to MS including Body Weight, BMI; Waist Circumference; Hip Circumference and Neck Circumference. Blood testing included fasting blood sugar, Liver function tests, Renal function tests. Other items related to Lipid metabolism included total cholesterol (TC), Triglycerides (TG), Low density (LDL) and high-density lipoprotein cholesterol (HDL), and non-high-density lipoprotein cholesterol. Adiponectin and some immune cytokines were also taken. Fibroscan of the liver was done at baseline and final visit. The Quality of life was checked with the standard SF-36 scoring sheet.

Primary Outcome

The primary outcome included the decline of Body Weight, Waist Circumference and Lowing of blood triglyceride TG.

Statistical Analysis

Excel 2016 (Microsoft Corp, Redmond WA) was used for data entry. Statistical analysis was performed using SPSS Base System ver. 25 (IBM SPSS Inc., Chicago IL.). Statistical analysis (descriptive statistics and Student t tests) was performed using SPSS ver. 22 (IBM SPSS Inc., Chicago IL.). Paired t-test was utilized to evaluate the difference between pretreatment mean and post-treatment mean. The percent changes in CAP Reading from baseline to 12 weeks of treatment with 2MSC were analyzed by using Chi-Square test.

Results

Compliance was excellent. No subject withdrew during study period. Adverse effects reported were all mild, including loose stools and mild abdominal discomfort. Liver and kidney functions remained normal. Bodily measurements all showed clear tendencies of improvement with convincing p values (Table 2).

Table 2: Changes of physical measurements of the volunteers.

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BW: Body Weight; BMI: body mass index.

The blood checking data indicative of lipid metabolism also showed very positive decline in the triglycerides (Table 3). Fibroscan study showing the “rigidity” of the liver through the anterior abdominal wall, demonstrated softening from 315.3 (49.7) to 291.0 (44.1) p=0.006 (Table 3).
Results of fibroscan for fatty liver study gave an overall positive effects of the herbal formula slowing down the progress of liver fibrosis when the controlled attenuation parameter (CAP) data revealed by the fibroscan were analyzed (Figure 1).

Table 3: Changes in the lipid profile and Fibroscan after administration of 2MSC.

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TC, total cholesterol; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; * 12-week minus Baseline.

Figure 1: Overall Fibroscan Results: Comparission of controlled attenuation parameter (CAP) values.

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Figure 2: Comparison of CAP Reading.

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When the liver conditions of the volunteers were classified into four different groups of liver steatosis, as: minimal, mild, moderate and severe, it was interesting to find that the herbal formula influenced only the moderate group significantly, while the minimal to mild group and severe group were unaffected. (Figure 2).

Discussion

Functional foods or nutraceuticals which have potential anti-obesity properties have attracted great attention. Schisandrae Fructus is a Chinese herb traditionally used as a liver tonic. Silymarin, an extract of the milk thistle (Silybum marianum), is a dietary supplement that is widely used in Europe for the prevention and treatment of liver problems. Crataegus Fructus (hawthorn) is traditionally used to promote digestion and dissipate food stagnation. Momordica charantia (bitter melon) is traditionally used for the treatment of diabetes in Ayurvedic Medicine. Our in vitro results suggested Crataegus Fructus aqueous extract exerted potent inhibitory effects on 3T3-L1 preadipocytes differentiation and cholesterol uptake into Caco-2 cells. Schisandrae Fructus aqueous extract and milk thistle exerted inhibitory effects on oleic acid-induced fatty liver in HepG2 cells. Momordica charantia extract on the other hand, exerted significant inhibitory effects on the glucose uptake into BBMV. Our in vivo results showed that our herbal formula exhibited a trend to reduce diet-induced increase in body weight and fat pad mass (epididymal, perirenal and inguinal fat). It also significantly reduced diet-induced increase in liver weight, liver lipid, and plasma lipid dose-dependently. High-fat diet induced a significant reduction in adiponectin level which was significantly improved by herbal formula supplementation at 4%. The herbal formula also significantly reduced diet-induced inflammation in the liver at both doses.

Metabolic Syndrome is currently understood as a combination of commonly co-existing symptoms some of them clearly present uniquely as an outstanding disease, like diabetes mellitus and hypertension, while others present as potentially threatening pathologies. Although adequate treatment for diabetes and hypertension are available, there is a common wish that they could be controlled at an early stage, so that progression could be curbed [23].
Apart from a rigidly followed lifestyle recommended for the cardiovascular system and obesity, which is not easy for the general public, food supplements have been used to help [24,25]. Our pilot clinical study ventured to develop an evidence-based supplement specific for MS, adopting a broad view covering all five problems: obesity, body weight, BMI, blood pressure, and blood lipids. Changes in liver fat and adiponectin were also explored [26,27]. Our pilot clinical study showed an overall body weight loss from 71.4 to 70.6 kg (p=0.027) and a BMI 28.0 to 27.7 (p=0.053) within a short period of 12 weeks.
The body circumference (external fat collection) shrinkage as detected through waist and hip also showed significant decline (p=0.014 and 0.011).
Since neck circumference measurement has recently been endorsed as a simple practical assessment for body fat, our neck measurements were supportive to the innovation and showed a 37.0 to 36.0 cm decline [28,29].
Useful results were provided in the blood tests. Liver function and renal function tests stayed normal, indicating the safety of the formula. With regard to the lipids: there were declines in triglycerages (p=0.044) and an increase in high density lipid (p=0.034) [30]. Fasting blood sugar remained stable.
The overall results were promising but the trial period lasted only 12 weeks and the number of volunteers was small. More than 50 Traditional Chinese Medicine formulae have been used to treat MS, basing on classical theory “Kidney Health”, cardiovascular support, and general harmonizing effects [31]. The 4-herbs selected to form the 2MSC formula were taken from classical recommendations subsequently scrutinized on bioactivity platform, to provide pharmacological evidence.
Liver scanning using Ultrasonic Fibroscan device is a simple qualitative and quantitative way to evaluate fat contents in the liver suspected of fatty changes. In our study, liver tissue resistance to Ultrasonic pressure was found to decline from 315.3 to 291.3 (p=0.010) within a period of only 12 weeks (Figure 1) (32-35). There are many reports on the study of non-alcoholic fatty liver in response to supplements [25,36-39] mainly targeting on the liver pathology alone. Our study took a broader view: other factors leading to MS should also be contributing towards fatty changes in the liver.
Since the discovery of Adiponectin as a factor very much affecting the Metabolism of fatty tissues responsible for the metabolic cycle connecting fat deposit and carbohydrate consumption, the behavior of adiponectin is often included in studies related to MS [40-43]. In our preclinical animal experimental study lasting 12 weeks, we found a high dose of the combined formula gave an increase of adiponectin suggesting that carbohydrates metabolism could have been promoted [19]. In our pilot clinical trial, however adiponectin was found to be either raised, remained stable or decreased. This might be due to the low dose effect or that the study lasting only 12 weeks. Using the SF36 questionnaire for the volunteers’ selfevaluation of their physical, mental and social well-being’s did not give remarkable results.

Conclusion

Up to today there is no FDA approved medications for the treatment of non-alcoholic fatty liver disease (NAFLD). The American Association for the Study of Liver Diseases (AASLD) suggested the combination use of vitamin E (an antioxidant) and pioglitazone may be helpful but not all patients would benefit from it. For patients diagnosed with NAFLD, the first line of treatment usually involves weight loss through a combination of a healthy diet and exercise. According to the AASLD guidelines, it was recommended that 10% body weight loss would lead to improvement of the steatosis and inflammation related. Previous studies also found that lifestyle modification could significantly improve the mean fibroscan CAP value (278.57±49.13 dB/m VS 252.91±62.02 dB/m, p=0.03). Thus 6 months of lifestyle modification which include moderate intensity physical exercise 3 days per week each for 45 minutes; plus a restricted caloric intake of 25-30 kcals/kg/day could better protect liver health after tremendous individual efforts and This obviously involves hard work and determination.

Our efforts on the creation of an Evidence-Based Specific Supplement for the control of Metabolic Syndrome have harvested highly positive data in the laboratory and in the subsequent 3 months’ pilot clinical trial. Encouraging results were obtained in the control of blood lipids, general body measurements and liver fibrosis. It is envisaged that coupled with more exercises and dietary control, better results could be expected. Further clinical studies would be very much warranted.

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Friday, February 4, 2022

Lupine Publishers| Diabetes in Older People: Comprehensive Approach

 Lupine Publishers| Journal of Diabetes and Obesity



Abstract

The clinical management of older people with diabetes requires a comprehensive evaluation and a holistic approach for the individualization of objectives and strategies of treatment. In older people with diabetes, geriatric syndromes, frailty and sarcopenia are considered at present as a third category of chronic complications. These situations are added to traditional microvascular and macrovascular complications, leading to significant disability and increasing the costs. In this context, two clinical scenarios can be considered: the first one, elderly subjects without significant comorbidities and good functional condition, in which an approach to diabetes similar to that of younger patients must be made. The second scenario, elderly and frail subjects, in which it will be essential a correct identification of these conditions and the evaluation of geriatric syndromes. This evaluation will guide the adaptation in the goals of treatment and in global management of diabetes.
Some basic principles should guide our decision-making: starting drugs at low - medium doses, with progressive increase according to tolerability; selection of drugs according to evidence-based medicine (considering the limited evidence in this age group), favoring agents with the lowest risk of hypoglycemia, avoid polypharmacy. Finally, patient´s safety and quality of life should be the main objectives.

Keywords: Diabetes; Older; Frailty; Evidence-Based-Medicine

Opinion

Clinical management of older diabetes people requires a comprehensive evaluation and a holistic approach for the individualization of objectives and strategies of treatment. Geriatric syndromes, frailty and sarcopenia are considered at present as a third category of chronic complications [1]. These situations are added to traditional microvascular and macrovascular complications, leading to significant disability and a significant increase in costs.
In this context, two clinical scenarios can be considered: first, elderly subjects without significant comorbidities and without frailty, in which an approach to diabetes similar to that of younger patients must be made. The second scenario, elderly and frail subjects, in which a correct identification of frailty and an evaluation of geriatric syndromes is mandatory, guiding modifications in the goals of treatment and in the global management of diabetes.

Initial Approach

1. Consider evaluation of medical, functional (self-care skills) and geriatric sphere to establish a frame of reference that determines the objectives and therapeutic strategies diabetes management (Evidence B) [2].
2. Assess presence of geriatric syndromes (polypharmacy, cognitive impairment, depression, urinary incontinence, falls, chronic pain) as conditions that interfere with patient’s management of diabetes and reduce quality of life (Evidence B) [2].

Figure 1: Comprehensive approach in older people with T2DM.
Bold therapy: grade A evidence. * Clinical situation: Intermediate / complex HbA1c 7-8%, TA <140/90 mmHg; very complex HbA1c <8.5%, TA <150/90 mm Hg.
ASA, acetylsalicylic acid; BP, blood pressure; LDLc, LDL cholesterol; y., every “number” years; eGF, estimated glomerular filtration; ACR, urine albumin creatinine ratio; HF, heart failure (evidence limited to patients at risk of heart failure or patients with FH diagnosis and reduced ejection fraction); Ŧ eGFR <30 mL/min/1.73 m2: Initiation not recommended, but once established, it can be maintained until the start of dialysis.
GLP1ra, glucagon-like peptide-1 receptor agonists; SGLT2i, sodium-glucose transport protein 2 inhibitors; DPP4i, dipeptidyl peptidase 4 inhibitors; Glarg, glargine

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3. Evaluation of frailty. The most validated and simple evaluation tools are Fried criteria and FRAIL scale. Consider potentially reversible causes that contribute to frailty such as presence of hypothyroidism, vitamin D deficiency, anemia, etc., is advised [3].
4. In those over 65 years of age, an early diagnosis of mild cognitive alterations is recommended, at diagnosis and subsequently annually [2]. Pfeiffer questionnaire or Minimental test are validated tools. In patients with cognitive dysfunction, simplify treatment, and adapt care structure.
5. Patient safety, preferences and quality of life should be the main objectives.
Treatment objectives, therapeutic approach and the assessment of comorbidities, are shown in (Figure 1).

Treatment Objectives (ABCDEH):

A. Glycemic control (A1c)

General recommendation, which should always be individualized, is a target of HbA1c 7.5-8.5% (58-69 mmol/l) in advanced frailty, and HbA1c 7-8% (53-64 mmol/l) in mild to moderate frailty. In frailty subjects, HbA1c <7% (53 mmol/l) should be avoided, especially if drugs with risk of hypoglycemia are used [2]. Many frail subjects have medical conditions that can interfere with HbA1c determination (chronic kidney disease, anemia, transfusions), and capillary blood glucose measurement may be necessary for assessing glycemic control [2].

B. Blood pressure (BP)

The objective of elderly subjects with diabetes, including those with dementia, is <140/90 mmHg, avoiding values <120/70 mmHg. A goal of <150/90 mmHg may be more suitable for the frail and dependent elderly. Whenever possible, measure BP standing and sitting, to detect orthostatic hypotension that increase the risk of falls. Withdrawal of treatments should be evaluated as frailty progresses [2,3].

C. Hypercholesterolemia

Statin treatment is recommended in the same situations as in non-elderly subjects: secondary prevention and primary prevention with high cardiovascular risk. Treatment of hypercholesterolemia in elderly patients has some differential characteristics. Lifestyle changes may not be possible. Furthermore, statin myopathy is more frequent (up to 10%) due to sarcopenia, so it is advisable to use low or moderate doses of statins. Treatment of vitamin D deficiency can improve statin-associated myalgia [3]. In situations of advanced frailty and dependency, suspension of statins may be considered.

D. Assessment of chronic complications

It must be individualized, with particular attention to those with higher influence on functional state (retinopathy, diabetic macular edema and diabetic foot). Heart failure, chronic kidney disease, and vitamin B12 deficiency should not be forgotten [2,4].

E. Geriatric Evaluation

Consider the assessment of geriatric syndromes: polypharmacy (use of three or five drugs simultaneously or the need to indicate one drug to supply the side effects of another), cognitive impairment, depression (Yesavage scale annually), urinary incontinence, falls, chronic pain (visual analogue pain scale), and frailty [2,3].

F. Hypoglycemia

In older people prevention of hypoglycemia is especially important because of the repercussions on the risk of falls, fractures, and emergency department visits and hospitalization. Elderly patients have impaired recognition of hypoglycemia and difficulties in acquiring basic skills for self-care and for resolution of hypoglycemia, which determines a greater severity of the episodes. Also, there is a bi-directional relationship between hypoglycemia and cognitive decline [5].

Comprehensive Pharmacological Treatment in the Elderly with T2DM

In general terms, disease modifying therapies should be used in combination with metformin, that is, with benefit in morbidity - associated mortality, low risk of hypoglycemia, and benefits in terms of control of BP and excess of weight (if appropriate) [6].
The patient and their caregivers should be aware of the “sick days” rule for metformin and sodium-glucose transport protein 2 inhibitors (SGLT2i), to avoid the potential risk of impaired renal function, lactic acidosis, and euglycemic ketoacidosis. Also, simplification of complex regimens is recommended, especially in patients with insulin therapy, to reduce the risk of hypoglycemia and polypharmacy, always based on individualized HbA1c targets.
The use of SGLT2i in frail elderly patients with a diagnosis of heart failure (HF) with reduced ejection fraction (FEr), is a reasonable therapeutic option, given its potential benefits. Diuretic and blood pressure treatment must be revised to avoid volume depletion (hypotension, orthostatic hypotension, dizziness, syncope, and dehydration), and impaired kidney function.
DPP4 inhibitors (DPP4i) may be reserved for elderly people with renal function contraindicating other therapies, or those patients with normal weight, in whom the additional weight loss may be a problem; in this case, sitagliptin [7]. and linagliptin [8] must be prioritized. Sulfonylureas and glinides (hypoglycemia risk), and pioglitazone (risk of heart failure and fractures), must be avoided.
In frail elderly people with obesity, the use of weekly glucagonlike peptide-1 receptor agonists (GLP1ra) may be a good option given the low risk of hypoglycemia, the weight loss benefit, the potential benefits in comorbidities and the weekly administration [9]. Its use must be accompanied by adapted nutritional therapy, and appropriate physical activity recommendations (aerobic and resistance training) to avoid the loss of muscle mass, including strength, flexibility and balance exercises [10]. Also, the appearance of gastrointestinal effects should be monitored.

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Friday, December 10, 2021

Lupine Publishers| Identification of The Downregulation of TPD52-Like3 Gene and NKX2-1 Gene in Type 2 Diabetes Mellitus Via RNA Sequencing

 Lupine Publishers| Journal of Diabetes and Obesity


Abstract

A recent study using next-generation RNA sequencing was reported on genome-wide changes in gene expressing in the skin between patients with type 2 diabetes mellitus, compared to non-diabetic patients. Ex-post review, based in part on both the existence of lipid droplets, peridroplet mitochondria and cytoplasmic mitochondria, selected in the gene metabolism category the most downregulated gene TPD52L3, and in the gene regulation category the most downregulated gene NKX2-1. There is strong evidence that these two genes are involved in the disease process of type 2 diabetes mellitus.

Keywords: Gene Expression; Lipid Droplets; Mitochondria; RNA Sequencing; Type 2 Diabetes Mellitus

Opinion

In an earlier study, it was proposed that the final consequence of hereditary anomaly results in the development of type 2 diabetes, which already emerges in the prediabetic phase. It was thought to occur due to an increased flux, as compared to the healthy controls where protons (H+-ions) from the mitochondrial intermembranespace re-enter the matrix via uncoupling protein-1 (UCP1). This causes hyperthermia in and around the mitochondria [1].
But the key question that remains to be answered here is for the connection between the increased flow of protons and type 2 diabetes mellitus. In the past decade, a study reported on the visual documentation of the possible interaction of lipid droplets with mitochondria. This interaction was found to be quite intimate with the involvement of membrane attached receptor proteins such as SNAP23 [2]. Also, the cellular population of mitochondria in brown adipocytes tissue could be divided into two subpopulations; i.e. mitochondrial population having physical evidence of adherence to a lipid droplet or peridroplet mitochondria, and a non-lipid droplet-bound cytoplasmic mitochondrial population without any adherence to lipid droplets [3,4].
Although both the peridroplet mitochondria and cytoplasmic mitochondria are similar in their cell membrane composition they differ in other fundamental respects [3,4]. A comparison of the purified peridroplet mitochondria to cytoplasmic mitochondria suggests that peridroplet mitochondria are more elongated, whereas cytoplasmic mitochondria tend to be smaller. Also, peridroplet mitochondria have enhanced oxidative phosphorylation capacity, TCA cycle activity, ATP synthesis, as well as increased ATP-dependent triglyceride synthesis compared to cytoplasmic mitochondria. The measured fatty acid-driven respiration and UCP1 content in the isolated mitochondria suggests that for thermogenic fat oxidation peridroplet mitochondria are not specialized compared to cytoplasmic mitochondria [3]. This signifies that, under healthy conditions, in the peridroplet mitochondria the protons derived from free fatty acids (FFAs) and generated by the electron-transport chain during the oxidation process of FA are used for the production of ATP without any escape of protons via UCP1 to produce heat. On the other hand, the protons generated by the oxidation of cytoplasmic mitochondrial FA are mainly used for the production of heat. So, peridroplet mitochondria have an increased coupled respiration, while cytoplasmic mitochondria have an increased uncoupling activity. The existence of peridroplet mitochondria demonstrates that the essential processes of fat metabolism can be selectively confined to exclusive and segregated subsets of mitochondria. The fatty acids intended for storage undergo synthesis of triacylglycols followed by their storage in the lipid droplets.

Most eukaryotic cells can store lipids in the form of droplets [5]. Lipid droplets are cytosolic storage organelles at the center of the lipid and energy homeostasis. They have a unique architecture consisting of a hydrophobic core of neutral lipids, mostly triacylglycerol and sterol esters and are enclosed by a phospholipid monolayer membrane. This single layer is derived from the endoplasmic reticulum, whereby triacylglycerols are synthesized between the two leaflets of the endoplasmic reticulum membrane. Associated with the monolayer is a specific set of proteins, which decorates the surface of the lipid droplet but is absent from the hydrophobic core [6]. These proteins associate with the membrane through hydrophobic hairpins, amphipathic helices and fatty acid modifications, and are also thought to control lipid droplet positioning inside the cell and association with other organelles.
In 2016, researchers demonstrated that the exogenous expression of human tumor protein D52 (TPD52) in the cultured 3T3 cells result in a significant increase in the numbers of lipid droplets [7]. Starting with the bulging of a triglyceride lens within the endoplasmic reticulum bilayer, lipid droplet biogenesis factors including TPD52 are recruited to the lens structure and facilitate the growth of the nascent lipid droplet [8,9]. Moreover TPD52- expressing 3T3 cells form more lipid droplets following oleic acid supplementation, which contributes to the lens formation [10]. As a previous study has shown, an increase in carbon-carbon double bonds in the acyl chains of phospholipids promotes the flexibility of cellular membranes [11]. So, TPD52 expression increases lipid storage, co-distributes with lipid droplets and is recruited to lipid droplets to stabilize lipid droplets [12]. Moreover, it is interesting to note that TPD52 knockdown decreased both lipid droplet sizes and numbers [12].
Tumor protein D52 is the founding member of the TPD52-like protein family representing four paralogous mammalian genes, i.e. TPD52, TPD52L1, TPD52L2, and TPD52L3 [7,13,14]. The group of Cao demonstrated that human TPD52L3 interacted with itself and with TPD52, TPD52L1, and TPD52L2 [14]. The four human linear proteins of this family are TPD52, TPD52L1, TPD52L2, and TPD52L3, which consist of 184, 204, 206, and 140 amino acid residues, respectively. Their first exon-coded protein located at the N-terminal side is unique to each isoform, and all the members contain a highly conserved coiled-coil motif located towards the N-terminus which is required for homo- and heteromeric interaction with other TPD52-like proteins [14,15] and share a sequence identity of ~50% [7]. Byrne et al. proposed that TPD52 may exert and/or regulate its activities through interaction with itself and its related proteins [15]. The coiled-coils were predicted by use of pairwise residue correlations and were not based on their crystal structures [16].

Figure 1: Alignment of the human TPD52 (upper row) and the human TPD52L3 (lower row) protein sequences. Amino acid residues are indicated by single letters. Vertical lines indicate identical residues and colons/dots indicate highly/weakly conserved residues.

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The analysis was focused on the sequences of TPD52 and TPD52L3. The two sequences revealed an obvious similarity, they share 63 identical positions and 42 similar positions resulting in an overall homology of 57.1% (Figure 1). The coiled-coil motif near the N-terminus was found in all TPD52-like proteins. Uniprot predicts a coiled domain for residues 28-57 of TPD52L3, and also for residues 21-70 of TPD52 [17]. The common part of these two coiled-coil protein sequences has an overall homology of 67.9% (Figure 1). The information regarding the amino acid sequences of human TPD52 (P55327-2) and TPD52L3 (Q96J77-1) was retrieved from the UniProtKB/Swiss-Prot databank. Interestingly, although the coiled-coil motif is very important for the interactions mediated by TPD52-like proteins [15,18], the TPD52L3 shortened coiled-coil motif successfully interacted with TPD52-like proteins.

A recent study using next-generation RNA sequencing was reported on genome-wide changes in gene expression in the skin between patients with type 2 diabetes mellitus, compared to nondiabetic patients [19]. The most downregulated gene of patients with type 2 diabetes in the gene metabolism category is TPD52L3 with a “log2 fold change” value of -28, compared to skin samples from non-diabetic patients. So far, this gene has not been linked to type 2 diabetes or wound healing.

The fact that the exogenous expression of human TPD52 increases the number of lipid droplets [7], TPD52 knockdown decreases the number of lipid droplets [12], and the activity of TPD52 depends on the interaction with TPD52L3 [14], support the idea that the major function of TPD52L3 is the lipid storage at the center of the lipid and energy homeostasis [8,9]. In other words, in brown adipocytes tissue, it seems likely that the significant downregulation of TPD52L3 causes a reduction in the number of lipid droplets in the skin samples of type 2 diabetes mellitus patients.

This indicates that an essential reduction in the lipid droplets suggests a substantial decrease in the peridroplet mitochondria for patients with type 2 diabetes and consequently an increase in the saturated plasma FFAs. As the unsaturation index (UI; number of carbon-carbon double bonds per 100 fatty acyl-chains) of FFAs from human white fat cells is substantially lower compared to the UI of serum FFAs in the healthy controls (85.5 and 191.9, respectively), these events force a shift from unsaturated to saturated acyl chains in the phospholipids of both the erythrocyte and vascular membranes [20]. This reduction in UI translates into an increase in the attractive forces between the mutual membrane phospholipid acyl chains, which redistributes the lateral pressure profile of the cell membrane [21]. This redistribution reduces the pore diameter of the transmembrane glucose transport channels of all Class I glucose transporter proteins, leading to a marked reduction in the transmembrane glucose transport [22].

On the other hand, the increased uncoupling activity of the cytoplasmic mitochondria [4] takes up the remaining fatty acid oxidation, including the formation of protons. The rationale is that the overall balance between the number of protons which re-enter the matrix through ATP synthase on the one hand, and the number of protons which re-enter the matrix through UCP1 on the other hand, might shift to the latter side, which in turn promotes an increase in the production of heat. To keep a narrow range of mitochondrial temperature compatible with life, the slow-down principle enters into force, which also results in an essential reduction in UI [1]. This chain of events is a blueprint of the development of type 2 diabetes mellitus.

A second result of the earlier mentioned genome-wide analysis study is the most downregulated gene in the gene regulation category, NKX2-1, of type 2 diabetes patients with a “log2 fold change” value of -28 compared to skin samples from non-diabetic patients [19]. Notably, a study also reported a novel heterozygous mutation in exon 3 of the NKX2-1 gene, which is related to a reduction in the muscle mitochondrial respiratory chain complex activity, a characteristic of type 2 diabetes [23]. It is to be noted that the reduced mitochondrial activity is one of the characteristics of type 2 diabetes [24]. This may be in advance of the patients with type 2 diabetes mellitus as the reduced mitochondrial activity implies a reduction in heat production.

Finally, it is worth considering about the potential benefit of the use of (modified) synthetic TPD52L3 for combating the adverse effects of type 2 diabetes mellitus.

Briefly, the idea is that two genes are pertinently involved in the disease process of type 2 diabetes mellitus: one concerns the downregulation of human TPD52L3 gene expression, which yields a significant reduction in the lipid droplets, whereas the second one relates to the downregulation of human NKX2-1 gene expression which reduces the mitochondrial respiratory chain activity (Figure 2).

Figure 2: Although the results of genome-wide screen for type 2 diabetes susceptibility genes are still under debate, a refined working hypothesis proposes that the primary effect of the downregulation of the human genes TPD52L3 and NKX2-1 generates an increased flux of mitochondrial intermembrane-space protons through UCP1 into the matrix, which causes an increase of extra heat. This process initiates the slow-down principle. UCP: Uncoupling protein; FFA: Free fatty acid; GLUT: Glucose transporter.  

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Lupine Publishers| Semaglutide versus liraglutide for treatment of obesity

  Lupine Publishers| Journal of Diabetes and Obesity Abstract Background: Once weekly (OW) semaglutide is a glucagon-like peptide...